Regiospecific process for the preparation of 4-[1- (4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl] benzonitrile

ABSTRACT

A regiospecific process for the preparation of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile comprising reacting 4-halomethylbenzonitrile with 4-amino-1,2,4-triazole followed by deamination and reaction with 4-fluorobenzonitrile.

FIELD OF THE INVENTION

The present invention relates to a regiospecific process for thepreparation of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, free of isomeric and triaryl impurities.4-[1-(4-cyanophenyl)-1-(1,2,4-triazol -1-yl)methyl]benzonitrile orLetrozole (INN name) is an antineoplastic agent.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,978,672 (referred to herein as '672, Indian Referencenot available) provides4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and theprocess of its preparation. The patent discloses reacting4-bromomethylbenzonitrile with 1,2,4-triazole to yield4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile.4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with4-fluorobenzonitrile to give4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile. Thispatent does not disclose the purity of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compoundof formula 1. When we followed the patented process we also get theunwanted isomer 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compoundof formula 4 (20 to 40%) in step 1. When the reaction mixture of step 1is treated with 4-fluorobenzonitrile it yields4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]-benzonitrile, acompound of formula 1, and its isomer, a compound of formula 5. Thus theimpurity of formula 4 has to be separated before treating it with4-fluorobenzonitrile, which involves an additional step of columnpurification, which is reported in '672 and makes the process tediousand commercially unviable.

Further, if the intermediate contains an impurity like 4-toluonitrile orother related impurities, that are present in the raw material viz.4-(bromomethyl)benzonitrile, in step 2, the impurities would participatein the reaction with 4- fluorobenzonitrile leading to the formation of4-[1,1-Bis(4-cyanophenyl)methyl]benzonitrile (referred to herein as‘tris impurity’) compound of formula 6 and other side products.

OBJECTS OF THE INVENTION

The object of the present invention is to provide a regiospecificprocess for the preparation of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl) methyl]benzonitrile, acompound of formula 1, free of impurities viz.4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-4-yl)methyl]benzonitrile, compoundof formula 5, and 4-[1,1-Bis(4-cyanophenyl)methyl]benzonitrile compoundof formula 6.

Another object of the present invention is to provide a regiospecificprocess for the preparation of4-[1-(1H-1,2,4-triazol-1-yl)methylene]benzonitrile, a compound offormula 3, substantially free of compound of formula 4 by eliminatingthe formation of an unwanted isomer.

Yet another object of the present invention is to purify theintermediate compound of formula 2, which is a precursor to theregioselective isomer using simple purification technique, in order toeliminate all the impurities, which would be present in its raw materialand yield compound of formula 1 free of also the ‘tris impurity’compound of formula 6.

SUMMARY OF THE INVENTION

The regiospecific process for preparation of4-[1-(4-cyanophenyl)-1-1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, said process comprising

-   -   (a) reacting 4-halomethylbenzonitrile with        4-amino-1,2,4-triazole to give        4-[(4-amino-4H-1,2,4-triazolium-1-yl)methyl]benzonitrile halide,        a compound of formula 2;

-   -   (b) deaminating the compound of formula 2 to        4-[1-(1H-1,2,4-triazol-1-yl)methylene]benzonitrile, a compound        of formula 3; and    -   (c) reacting the compound of formula 3 with        4-fluorobenzonitrile.

The present invention also provides a regiospecific process for thepreparation of compounds of formulae 2 and 3 and simple purification ofcompound of formula 2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a regiospecific process for thepreparation of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, substantially free of impurities starting with4-amino-1,2,4-triazole in which the possibility of 4-alkylation isblocked by an amino group. This eliminates the formation of the unwantedimpurity 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compound offormula 4, which leads to the impurity, a compound of formula 5, in thefinal stage preparation of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compoundof formula 1.

The process of the present invention provides4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, substantially free of impurities. The impuritiesmay be 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-4-yl)methyl]benzonitrile,compound of formula 5, and/or4-[1,1-Bis(4-cyanophenyl)methyl]benzonitrile, compound of formula 6.

4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compoundof formula 1, provided by the process of this invention has puritygreater than 99.5%, preferably greater than 99.8%.

The regiospecific process of the present invention is carried out in 3steps by reacting 4-halomethylbenzonitrile with 4-amino-1,2,4-triazoleto obtain 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile halide,a compound of formula 2, deaminating to obtain4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile, a compound of formula 3,and reacting the compound of formula 3 with 4-fluorobenzonitrile toyield 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, substantially free of impurities.

According to one embodiment of the process of the present invention step(a) of the process is carried out by reacting 4-halomethylbenzonitrilewith 4-amino-1,2,-triazole by heating in a solvent selected from water,alcohols selected from alkyl, aryl or alkylaryl alcohols like ethanol,methanol, n-propanol, isopropanol, n-butanol, isobutanol, benzyl alcoholand the like; ketones selected from alkyl, aryl or alkylaryl ketonessuch as acetone, methylisobutyl ketone, methylethyl ketone,acetophenone; nitrites such as benzonitrile, acetonitrile; anddimethylsulphoxide, diphenylether, dimethylformamide, dichlorobenzeneand the like.

4-halomethylbenzonitrile may be selected from4-chloromethylbenzonitrile, 4-iodomethylbenzonitrile and4-bromomethylbenzonitrile, the preferred being4-bromomethylbenzonitrile.

According to the preferred process of the present invention step (a) ofthe process may be carried out in an alcoholic solvent like isopropanol.

The process of the present invention step (a) is carried out attemperatures ranging from about 20 to 150° C., preferably about 75 to100° C., the most preferred being about 80 to 85° C.

The process of the present invention step (a) is carried out for about 3to 8 hours, preferably about 4 to 6 hours, the most preferred beingabout 5 hours.

The reaction mixture on completion of the reaction is cooled andfiltered. The compound of formula 2 obtained may be purified by standardtechniques known to those skilled in this art for instance, simpleleaching with solvents like ketones, nitrites, esters, ethers,preferably alcohols and alkanes, most preferred being isopropanol andhexane to give pure compound of formula 2.

According to another embodiment of the process of the present inventionstep (b) is carried out by deaminating compound of formula 2 using anydeaminating agent like (i) nitrites which may be selected from inorganicnitrites of sodium or potassium, and organic nitrites such as alkylnitrites, preferably sodium nitrite is used; or (ii) nitrous acid. Thepreferred deaminating agent being nitrous acid. Nitrous acid may beprepared insitu by reacting inorganic nitrite with mineral acid.

In the preferred process of the present invention step (b) is carriedout by deaminating compound of formula 2 with sodium nitrite in thepresence of mineral acid like hydrochloric acid under cold conditionsabout 0 to 5° C. over a period of about 6 to 8 hours.

The reaction mixture may be worked up by standard techniques known tothose skilled in this art. For instance, the unreacted nitrous acid isdecomposed with urea at the end of the reaction and impurities removedby extraction with a solvent selected from halo substituted orunsubstituted alkyl and aryl hydrocarbons such as hexane, toluene,xylenes, methylene chloride, chlorobenzene and the like, alkyl or arylketones like methylisobutyl ketone, and the like, preferablydichloromethane.

The aqueous solution is adjusted to pH>8 with a base. Preferable basebeing an aqueous ammonical solution.

After adjusting the pH compound of formula 3 is extracted with a solventselected from halo substituted or unsubstituted alkyl and arylhydrocarbons such as hexane, toluene, xylenes, methylene chloride,chlorobenzene and the like, alkyl or aryl ketones like acetone,methylisobutyl ketone, and the like, preferably dichloromethane. Theorganic layer containing the compound of formula 3 is washed with waterand then concentrated by heating and/or applying vacuum to give a syrupyliquid. The syrupy liquid is then converted to a solid by adding asolvent mixture of two or more solvents selected from halo substitutedor unsubstituted alkyl and aryl hydrocarbons such as hexane, toluene,xylenes, methylene chloride, chlorobenzene and the like, alkyl or arylketones like acetone, methylisobutyl ketone, methylethyl ketone and thelike, alky or aryl alcohols like ethanol, methanol, isopropanol, benzylalcohol and the like, alky or aryl nitriles like benzonitrile,acetonitrile and the like, preferably isopropanol and hexane mixture.The volume ratio of isopropanol to hexane may vary from 10:90 to 90:10,preferably 50:50, the most preferred being 20:80.

The solution containing the solids is cooled to below 25° C., preferably8-10° C., stirred, filtered and washed with an aprotic solvent selectedfrom aliphatic hydrocarbons, aromatic hydrocarbons and the like, mostpreferably hexane to yield a compound of formula 3.

The compound of formula 3 obtained by the process of the presentinvention is free of its isomer, compound of formula 4.

According to yet another embodiment of the process of the presentinvention step (c) is carried out by treating the compound of formula 3with 4-fluorobenzonitrile to yield4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1, substantially free of impurities in an organicsolvent such as dimethylformamide in the presence of a base such aspotassium tertiary butoxide at lower temperatures such as −5 to −10° C.

The reaction mixture is worked up by standard techniques known to thoseskilled in this art. For instance, at the end of the reaction thereaction mixture is worked up by extracting with an organic solvent,concentrating, and optionally purifying to yield4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile,acompound of formula 1, substantially free of impurities. The purifyingmethods may be selected from washing, extracting, suspending,precipitating, leaching, recrystallizing and the like. Preferably,recystallization of compound of formula 1 with a solvent selected frompolar and non-polar solvents such as alcohols, ketones and esters,preferably esters, the preferred being ethyl acetate.

Methods of preparing4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile aredisclosed in U.S. Pat. No. 4,978,672 (Indian Reference not available).

The invention is illustrated but not restricted by the description inthe following example.

EXAMPLES Example 1

(a) Preparation of 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrilebromide, compound of formula 2:

4-bromomethylbenzonitrile (300.0 gm, 1.530 moles) was heated with4-amino-1,2,4-triazole (141.5 gm, 1.683 moles) in isopropanol (3.0 L) asa solvent for 5.0 hours at 80°-85° C. temperature. Reaction mixture wascooled gradually to room temperature and further to 0°-5° C. temperatureand stirred for 2.0 hrs and filtered.

(b) Purification of4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide, compoundof formula 2:

The filtered solid was washed with isopropanol (300.0 ml) followed byhexane (300.0 ml), gave 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide, compound of formula 2. (310.0 gm, 72.2% yield).

(c) Preparation of 4-11-(1,2,4-triazol-1-yl)methyll benzonitrile,compound of formula 3:

4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide (275.0 gm,0.982 moles) was dissolved in water (1.1 L) and cooled to 0°-5° C.temperature. To this solution, was added hydrochloric acid (196.5 ml,1.963 moles) at 0°-5° C. temperature followed by solution of sodiumnitrite (74.5 gm, 1.080 moles) in water (275.0 Ml) at 0°-5° C.temperature within 6.0 hrs, followed by stirring at 30°-35° C.temperature for 2.0-3.0 hrs. After reaction was over, unreacted nitrousacid was decomposed with urea, extracted with dichloromethane to removeimpurities. Finally, aqueous layer was basified to pH 8.0-8.5 by adding25% ammonia solution and product was extracted with dichloromethane Anorganic layer containing product was washed with water and concentratedto give syrupy liquid, to which was added isopropanol:hexane (20:80),slurry so obtained was cooled to 8-10° C. temperature, stirred for 2.0hrs, filtered and washed with hexane (75.0 ml) to give4-[1-(1,2,4-triazolyl)methyl]benzonitrile,compound of formula 3 free ofcompound of formula 4. (150.0 gm, 82.9% yield)

(d) Preparation of4-[1-(4-cyanophenyl)-1-(1,2,4triazol-1-yl)methyl]benzonitrile, compoundof formula 1:

The solution of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (100 gm, 0.543moles) in N,N-dimethylformamide (500 ml) was added at −10° to −5° C.temperature to the solution of potassium tertiary butoxide (122 gm,1.085 moles) in N,N-dimethylformamide (750 ml) and stirred for 1.0 hour.To this solution, was added a solution of 4-fluorobenzonitrile (77 gm,0.592 moles) in N,N-dimethylformamide (500 ml) at −10° to −5° C.temperature and stirred for 3.0 hours. Reaction mixture was thenneutralized to pH 7.5-8.0 by adding 1.0 N hydrochloric acid (700 ml) andconcentrated to remove N, N-dimethylformamide under vacuum. To theresidue was added water and product was extracted with ethyl acetate. Anorganic layer was washed with water and concentrated under vacuum. Tothe residue was added, isopropyl alcohol, stirred for 1.0 hour andfiltered the crude product (125.0 gm). Crude product was recrystallizedfrom hot ethyl acetate (1.37 L) to give4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compoundof formula 1. (90 g, 58 % yield, 99.90% HPLC purity).

1. A regiospecific process for preparation of4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, acompound of formula 1,

said process comprising: (a) reacting 4-halomethylbenzonitrile with4-amino-1,2,4-triazole to give4-[(4-amino-4H-1,2,4-triazolium-1-yl)methyl]benzonitrile halide, acompound of formula 2,

deaminating the compound of formula 2 to4-[1-(1H-1,2,4-triazol-1-yl)methylene]benzonitrile, a compound offormula 3,

(c) reacting the compound of formula 3 with 4-fluorobenzonitrile.
 2. Aprocess as claimed in claim 1 wherein in step (a) the4-halomethyl-benzonitrile is 4-bromomethylbenzonitrile.
 3. A process asclaimed in claim 1 wherein step (a) is carried out in the presence of asolvent selected from an alcohol.
 4. A process as claimed in claim 3wherein the alcohol is isopropanol.
 5. A process as claimed in claim 1wherein step (a) is carried out at a temperature from about 20 to 150°C. for about 3 to 8 hours.
 6. A process as claimed in claim 1 whereincompound of formula 2 is further purified by leaching the product ofstep (a) with an organic solvent(s) selected from ketones, nitrites,esters, ethers, alcohols and alkanes or mixtures thereof.
 7. A processas claimed in claim 1 wherein step (b) is carried out by deaminating thecompound of formula 2 to4-[1-(1H-1,2,4-triazol-1-yl)methylene]benzonitrile, a compound offormula 3 with nitrous acid generated in situ with an inorganic nitriteand a mineral acid.
 8. A process as claimed in claim 7 wherein thecompound of formula 3 is free of its isomer, compound of formula 4;


9. A process as claimed in claim 1 further comprising purification ofthe compound of formula 1 wherein the said purification maybe selectedfrom the group consisting of washing, extracting, suspending,precipitating, leaching and recrystallizing.
 10. A process as claimed inclaim 9 wherein the compound of formula 1 is purified by recrystallizingfrom ethyl acetate.
 11. A process as claimed in claim 9 wherein4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile haspurity greater than 99.5%.
 12. A process as claimed in claim 9 wherein4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile is freefrom the impurities compounds of formulae 5 and 6;